Apoptosis, or programmed cell death, is a naturally occurring process that plays a strong role in ensuring the development and maintenance of multicellular organisms by eliminating unwanted cells. However, if this process goes over stimulated, cell loss and degenerative disorders such as rheumatoid arthritis, chronic heart, liver and renal failure, adult respiratory distress syndrome, cachexia caused by cancer, stroke, heart attack and heart failure can result. (Sharma R., and Anker S D, Int. J. Cardiol., 2002, 85:161–171, Argiles J M et al., Int. J. Biochem Cell Biol., 2003, 35:405–409, Castellanos M, et al., Stroke, 33:982–987, Cusack M R, et al., Amer. Coll. Cardiol., 2002, 39:1917–23, Agnoletti L. et al, Circulation, 1999, 100:1983–1991).
Mediators, which can trigger apoptosis include TNF alpha, Fas and transforming growth factor beta, neurotransmitters, growth factor withdrawal, loss of extracellular matrix attachment and extreme fluctuations in intracellular calcium levels (Afford and Randhawa, Mol. Pathol., 2000, 53:55–63). Among them TNF alpha killing pathways are considered as a most common route of apoptosis signaling. This cytokine is also involved in cancer related fatigue, leucopenia, anemia, and thrombocytopenia (Kurzrock R., Cancer, 2001, 92: 1684–8,). TNF alpha is also implicated in the development of the neurodegenerative disorders such as Alzheimer's and Parkinson's disease, ALS, rhinitis pigmentosa and multiple sclerosis (McGuire S O et al., Exp Neurol., 2001, 169:219–230). Its pathogenetic role is crucial in the development of the extensive brain, lung, and heart damage (Barone F. C. et al, Stroke, 1997, 28:1233–1244, Armstrong L. et al., Thorax, 1997, 52:442–446,). Plasma concentrations of TNF alpha are persistently elevated among patients after myocardial infarction (Ridker P., et al, Circulation, 2000, 101:2149–2153)
With the identification of the systemic TNF alpha response as a major component in the pathogenesis of the septic shock syndrome (Jaecshke H., et al J. Immunol., 1998, 160:3480–3486), much of the recent work has focused on modulating of this response. High-flow haemofiltration was offered to clean both endotoxin and cytokines (Sharma V K and Dellinger R P, Expert Opin Investig Drugs, 2003, 12:139–152). Hypotensive and proinflammotory effects of TNF alpha were inhibited by soluble receptors/receptor antagonists and anti-inflammatory cytokines such as interleukine10. The current experimental therapies involve transforming growth factor-beta, granulocyte colony-stimulating factor, interferon phi and anti TNF alpha antibody (Stamm Ch., et al, Circulation, 101, suppl. 1, 350–351). Moreover, less known cytokines such as macrophage migration inhibitory factor and high mobility group I protein will be clinically tested (Zanotti S., et al., Expert Opin Investig Drugs, 2002, 11:1061–75).
Another preliminary study has demonstrated that recombinant GM-CSF upregulates HLA-DR expression on monocytes, thus reversing the immunoparalysis in patients with severe sepsis. Moreover, there was a concurrent increase of whole blood TNF response. (Nierhaus A., et al. Intensive Care Med, 2003, 21).
The same situation was noticed in rats with burn shock. Nonsurvival group had lower levels of serum G-CSF and higher content of TNF alpha compared with survival. Supplement of GM-CSF could significantly improve animal survival with burn wound infection following severe burn shock (Yan R., et al. Zhonghua Zhen Xing Shao Shang Wai Ke Za Zi, 1997, 13:368–372). Serum TNF alpha was also elevated after soft tissue trauma and hemorrhagic shock, which leads to the acute respiratory distress syndrome (ARDS) {Jarrar D, et al. Am. J. Physiol. Lung Cell Mol. Physiol., 2002, 283:799–805}.
Ischemia/reperfusion (I/R) induces a cytokines response and production of reactive oxygen species, which affects the organs remote to the sites of I/R. Yet, hepatic TNF alpha was implicated in playing major role in the liver damage during renal surgery (Serteser M., et. Al., J. Surg Res, 2002, 107:234–40).
Intravenous injection of whole lactobacillus reduced tachyarrhythmia significantly and improved recovery of the ischemized rat heart (Oxman T., et al, Am J Physiol Heart Circ Physiol, 278, H1717–H1724).
However, a broad variety of biodegradable glucosaminemuramyl peptides were not isolated and tested for cytoprotective effects.